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PUBOURETHRAL LIGAMENT INJURY CAUSES LONG TERM STRESS URINARY INCONTINENCE IN FEMALE RATS
540
THE JOURNAL OF UROLOGY®
0(7+2'6 3%22ZDVFUHDWHGLQDGXOWPDOH1HZ=HDODQG White rabbits by 14-day partial urethral ligation and sham-operated animals served as controls. Bladder tissue from obstructed and control DQLPDOVZHUHXVHGIRUSURWHLQLVRODWLRQDQGSDUDI¿QVOLGHSUHSDUDWLRQ7KH H[SUHVVLRQDQGORFDOL]DWLRQRI%.FKDQQHOZHUHGHWHUPLQHGE\:HVWHUQ blot and immunostaining. Cultured human bladder smooth muscle cells were transfected with BK channel beta subunit siRNA to measure the effect of BK channel knockdown on MLC phosphorylation. RESULTS: (1) Both BK channel alpha and beta subunit were down-regulated in detrusor smooth muscle from PBOO animals. (2) BK channel beta subunit was distributed within the detrusor smooth muscle EXQGOH FRORFDOL]HGZLWKVPRRWKPXVFOHVSHFL¿FDOSKDDFWLQ %. channel alpha subunit was distributed in detrusor smooth muscle layer and submucosal area. (3) BK channel beta subunit siRNA transfection knocked out 70-80% expression of BK channel beta subunit in cultured cells which resulted in a higher basal MLC phosphorylation than normal control. (4) BK channel siRNA didn’t affect the expression of smooth muscle regulatory proteins (MLC kinase and Rho-kinase). CONCLUSIONS: This study shows that PBOO downregulates BK channel expression and down-regulation of BK channel increases 0/&SKRVSKRU\ODWLRQOHYHOZKLFKPD\EHGXHWRGHSRODUL]HGPHPEUDQH SRWHQWLDODQGDQHOHYDWLRQRILQWUDFHOOXODUFDOFLXP7KLV¿QGLQJIXUWKHU indicates that a high MLC phosphorylation is the underlying mechanism of detrusor overactivity and there are multiple factors that contribute to this increased MLC phosphorylation including the BK channel. Source of Funding: George O’Brien Urology Research Center Grant P50 DK52620.
1579 PUBOURETHRAL LIGAMENT INJURY CAUSES LONG TERM STRESS URINARY INCONTINENCE IN FEMALE RATS John C Kefer*, Guiming Liu, Firouz Daneshgari. Cleveland, OH. ,1752'8&7,21$1' 2%-(&7,9( 7KH HI¿FDF\ RI PLG XUHWKUDO VOLQJV LV EDVHG RQ WKH LQWHJUDO WKHRU\ RI GH¿FLHQF\ RI SXER urethral ligament (PUL) in women resulting in urethral hypermobility. :HK\SRWKHVL]HGWKDW38/LQMXU\LQWKHIHPDOHUDWFDXVHVVWUHVVXULQDU\ incontinence indicated by decreased leak point pressures (LPP), and have presented the short term results of PUL injury on LPP. Here we examine the long-term effects of PUL injury as a potential model for SUI and compare our model with an established model of SUI. METHODS: A total of 20 female age-matched SpragueDawley rats were randomly assigned to 1 of 3 groups: PUL-transection (PULT) with LPP measured at 28 days, sham-PUL transection with LPP measured at 28 days, and bilateral pudendal nerve transection (PNT) with LPP measured at 28 days post-op. PUL transection was performed under direct vision and LPP was measured 28 days later via an implanted suprapubic catheter. Wilcoxon rank sum tests were used to evaluate differences in LPP between the experimental groups. Following LPP, all DQLPDOVZHUHVDFUL¿FHGDQGWKHHQEORFPLGOLQHSHOYLFWLVVXHVLQFOXGLQJ urethra, vagina, and pubic arch underwent histological examination. 5(68/76 /33 ZDV VLJQL¿FDQWO\ GHFUHDVHG LQ WKH 38/7 group versus the sham group (15.7 cm ± 6.46 vs. 42.6 cm ± 12 cm H2O, p<0.001) and no different from PNT group (15.7 cm ± 6.46 vs.15.09 ± 4.98, p< 0.76), indicating durability of effects of PULT on inducing long term SUI in the female rat. Histological examination of the en-block VXSUDSXELF DUHDV FRQ¿UPHG DEVHQFH RI 38/ WLVVXHV LQ 38/7 JURXS with intact PUL in the sham and PNT groups. &21&/86,216 2XUUHVXOWVGHPRQVWUDWHWKDWGH¿FLHQF\RI the PUL in the female rat induces long term SUI that is comparable to the established SUI model of PNT. Our model offers a novel approach to investigating mechanisms of urethral hypermobility leading to SUI as well as potential therapeutic interventions for SUI. Source of Funding: None
Vol. 179, No. 4, Supplement, Tuesday, May 20, 2008
1580 ANALYSIS OF HEART RATE VARIABILITY (HRV) IN THE ASSESSMENT OF AUTONOMIC DYSFUNCTION IN MEN WITH LOWR URINARY TRACT SYMPTOM (LUTS) Jong B Choi*, Hyung-Jee Kim, Sun Kim, Sung H Park, Jong T Park, Young S Kim. Suwon, Republic of Korea, and Cheonan, Republic of Korea. INTRODUCTION AND OBJECTIVE: LUTS is a common disease but the etiology and mechanism are still unclear. We suppose that autonomic nervous dysfunction may be a causative factor because lower urinary tract is controlled through sympathetic and parasympathetic nervous system. Heart rate variability (HRV) is a tool to estimate autonomic nervous function, therefore we measured and compared parameters of heart rate variability between in men with LUTS and health normal group. METHODS: Electrocardiographic signals were obtained from 35 men with LUTS (mean age, 50.5 ± 14.9 years old), and 110 healthy men (mean age, 49.5 ± 5.19 years old) in resting state. We calculated the HRV indices with spectral analyses. High frequency (HF) power was used to index parasympathetic activity, whereas the ratio of low to high frequency power (LF/HF) was used to index sympathovagal balance. The parameters of HRV were compared with Mann-Whitney test using SPSS version 12. RESULTS: The results of parameters of HRV between groups (mean ± standard error) are followed. SDNN LUTS 28±2.3 Control 34±1.1 P value 0.007
RMSSD 21±2.4 24±1.0 0.069
HR 71±3.4 72±1.2 0.385
TP 652±133.3 933±65.1 0.003
VLF 379±97.6 505±35.8 0.009
LF 178±30.9 247±20.0 0.050
HF 98±16.9 181±15.5 0.004
LF/HF 2.5±0.36 2.2±0.21 0.22
CONCLUSIONS: Men with LUTS exhibited different HRV parameters compared with normal controls. These decreased values indicate that they may have some kind of disease or imbalance in the autonomic nervous system and it may be a clue that we should consider it the difference of LUTS from healthy men. Source of Funding: None
1581 MAJOR RISK FACTORS FOR NOCTURIA IN A POPULATIONBASED STUDY Kari A Tikkinen*, Anssi Auvinen, Jeffrey P Weiss, Mika A Ala-Lipasti, Tapani Keranen, Olli Polo, Teuvo L Tammela. Tampere, Finland, New York, NY, and Seinajoki, Finland. INTRODUCTION AND OBJECTIVE: We aimed to assess the major risk factors for nocturia. METHODS: Questionnaires were mailed to 6,000 Finns aged 18-79 years, randomly drawn from the Population Register. Nocturia was GH¿QHGDVYRLGVQLJKW XVLQJ'$1366DQG$8$6, 4XHVWLRQQDLUH contained items on physician-diagnosed diseases/conditions (40), use of prescribed medication (20), lifestyle factors (smoking, coffee, alcohol), DQG%0, QRUPDOZHLJKW%0, RYHUZHLJKWREHVH ,Q addition, urinary urgency (often or always, scale: never-rarely-oftenDOZD\V VWUHVVXULQDU\LQFRQWLQHQFH RIWHQRUDOZD\V DQGVQRULQJ nights/week) were considered as potential risk factors (using DAN-PSS and BNSQ). Age, socio-demographic and female reproductive factors (parity, menopause, hormone therapy, hysterectomy) were treated as potential confounders. All factors associated (p<0.10) with nocturia in the age-adjusted analyses were entered into the multivariate model. Backward elimination techniques were used to select variables for WKH¿QDOPRGHORIQRFWXULDZLWKOLNHOLKRRGUDWLRWHVWVXVHGWRGHWHUPLQH VLJQL¿FDQFH p<0.05). Then, elimination of confounders was performed FKDQJHLQWKHHVWLPDWHZDVGHHPHGFRQIRXQGLQJ 5(68/76 VXEMHFWV WRRN SDUW ZHUH excluded due to pregnancy, puerperium, or urinary tract infection. A number of conditions and medications were found as candidates for multivariate analysis. Several independent risk factors were found in the multivariate analyses (separately performed for men and women) (Table). Even though urgency was the strongest risk factor, majority of nocturia was not associated with urgency (Figure). Again, majority of urgency was associated with nocturia.
THE JOURNAL OF UROLOGY®
0(7+2'6 3%22ZDVFUHDWHGLQDGXOWPDOH1HZ=HDODQG White rabbits by 14-day partial urethral ligation and sham-operated animals served as controls. Bladder tissue from obstructed and control DQLPDOVZHUHXVHGIRUSURWHLQLVRODWLRQDQGSDUDI¿QVOLGHSUHSDUDWLRQ7KH H[SUHVVLRQDQGORFDOL]DWLRQRI%.FKDQQHOZHUHGHWHUPLQHGE\:HVWHUQ blot and immunostaining. Cultured human bladder smooth muscle cells were transfected with BK channel beta subunit siRNA to measure the effect of BK channel knockdown on MLC phosphorylation. RESULTS: (1) Both BK channel alpha and beta subunit were down-regulated in detrusor smooth muscle from PBOO animals. (2) BK channel beta subunit was distributed within the detrusor smooth muscle EXQGOH FRORFDOL]HGZLWKVPRRWKPXVFOHVSHFL¿FDOSKDDFWLQ %. channel alpha subunit was distributed in detrusor smooth muscle layer and submucosal area. (3) BK channel beta subunit siRNA transfection knocked out 70-80% expression of BK channel beta subunit in cultured cells which resulted in a higher basal MLC phosphorylation than normal control. (4) BK channel siRNA didn’t affect the expression of smooth muscle regulatory proteins (MLC kinase and Rho-kinase). CONCLUSIONS: This study shows that PBOO downregulates BK channel expression and down-regulation of BK channel increases 0/&SKRVSKRU\ODWLRQOHYHOZKLFKPD\EHGXHWRGHSRODUL]HGPHPEUDQH SRWHQWLDODQGDQHOHYDWLRQRILQWUDFHOOXODUFDOFLXP7KLV¿QGLQJIXUWKHU indicates that a high MLC phosphorylation is the underlying mechanism of detrusor overactivity and there are multiple factors that contribute to this increased MLC phosphorylation including the BK channel. Source of Funding: George O’Brien Urology Research Center Grant P50 DK52620.
1579 PUBOURETHRAL LIGAMENT INJURY CAUSES LONG TERM STRESS URINARY INCONTINENCE IN FEMALE RATS John C Kefer*, Guiming Liu, Firouz Daneshgari. Cleveland, OH. ,1752'8&7,21$1' 2%-(&7,9( 7KH HI¿FDF\ RI PLG XUHWKUDO VOLQJV LV EDVHG RQ WKH LQWHJUDO WKHRU\ RI GH¿FLHQF\ RI SXER urethral ligament (PUL) in women resulting in urethral hypermobility. :HK\SRWKHVL]HGWKDW38/LQMXU\LQWKHIHPDOHUDWFDXVHVVWUHVVXULQDU\ incontinence indicated by decreased leak point pressures (LPP), and have presented the short term results of PUL injury on LPP. Here we examine the long-term effects of PUL injury as a potential model for SUI and compare our model with an established model of SUI. METHODS: A total of 20 female age-matched SpragueDawley rats were randomly assigned to 1 of 3 groups: PUL-transection (PULT) with LPP measured at 28 days, sham-PUL transection with LPP measured at 28 days, and bilateral pudendal nerve transection (PNT) with LPP measured at 28 days post-op. PUL transection was performed under direct vision and LPP was measured 28 days later via an implanted suprapubic catheter. Wilcoxon rank sum tests were used to evaluate differences in LPP between the experimental groups. Following LPP, all DQLPDOVZHUHVDFUL¿FHGDQGWKHHQEORFPLGOLQHSHOYLFWLVVXHVLQFOXGLQJ urethra, vagina, and pubic arch underwent histological examination. 5(68/76 /33 ZDV VLJQL¿FDQWO\ GHFUHDVHG LQ WKH 38/7 group versus the sham group (15.7 cm ± 6.46 vs. 42.6 cm ± 12 cm H2O, p<0.001) and no different from PNT group (15.7 cm ± 6.46 vs.15.09 ± 4.98, p< 0.76), indicating durability of effects of PULT on inducing long term SUI in the female rat. Histological examination of the en-block VXSUDSXELF DUHDV FRQ¿UPHG DEVHQFH RI 38/ WLVVXHV LQ 38/7 JURXS with intact PUL in the sham and PNT groups. &21&/86,216 2XUUHVXOWVGHPRQVWUDWHWKDWGH¿FLHQF\RI the PUL in the female rat induces long term SUI that is comparable to the established SUI model of PNT. Our model offers a novel approach to investigating mechanisms of urethral hypermobility leading to SUI as well as potential therapeutic interventions for SUI. Source of Funding: None
Vol. 179, No. 4, Supplement, Tuesday, May 20, 2008
1580 ANALYSIS OF HEART RATE VARIABILITY (HRV) IN THE ASSESSMENT OF AUTONOMIC DYSFUNCTION IN MEN WITH LOWR URINARY TRACT SYMPTOM (LUTS) Jong B Choi*, Hyung-Jee Kim, Sun Kim, Sung H Park, Jong T Park, Young S Kim. Suwon, Republic of Korea, and Cheonan, Republic of Korea. INTRODUCTION AND OBJECTIVE: LUTS is a common disease but the etiology and mechanism are still unclear. We suppose that autonomic nervous dysfunction may be a causative factor because lower urinary tract is controlled through sympathetic and parasympathetic nervous system. Heart rate variability (HRV) is a tool to estimate autonomic nervous function, therefore we measured and compared parameters of heart rate variability between in men with LUTS and health normal group. METHODS: Electrocardiographic signals were obtained from 35 men with LUTS (mean age, 50.5 ± 14.9 years old), and 110 healthy men (mean age, 49.5 ± 5.19 years old) in resting state. We calculated the HRV indices with spectral analyses. High frequency (HF) power was used to index parasympathetic activity, whereas the ratio of low to high frequency power (LF/HF) was used to index sympathovagal balance. The parameters of HRV were compared with Mann-Whitney test using SPSS version 12. RESULTS: The results of parameters of HRV between groups (mean ± standard error) are followed. SDNN LUTS 28±2.3 Control 34±1.1 P value 0.007
RMSSD 21±2.4 24±1.0 0.069
HR 71±3.4 72±1.2 0.385
TP 652±133.3 933±65.1 0.003
VLF 379±97.6 505±35.8 0.009
LF 178±30.9 247±20.0 0.050
HF 98±16.9 181±15.5 0.004
LF/HF 2.5±0.36 2.2±0.21 0.22
CONCLUSIONS: Men with LUTS exhibited different HRV parameters compared with normal controls. These decreased values indicate that they may have some kind of disease or imbalance in the autonomic nervous system and it may be a clue that we should consider it the difference of LUTS from healthy men. Source of Funding: None
1581 MAJOR RISK FACTORS FOR NOCTURIA IN A POPULATIONBASED STUDY Kari A Tikkinen*, Anssi Auvinen, Jeffrey P Weiss, Mika A Ala-Lipasti, Tapani Keranen, Olli Polo, Teuvo L Tammela. Tampere, Finland, New York, NY, and Seinajoki, Finland. INTRODUCTION AND OBJECTIVE: We aimed to assess the major risk factors for nocturia. METHODS: Questionnaires were mailed to 6,000 Finns aged 18-79 years, randomly drawn from the Population Register. Nocturia was GH¿QHGDVYRLGVQLJKW XVLQJ'$1366DQG$8$6, 4XHVWLRQQDLUH contained items on physician-diagnosed diseases/conditions (40), use of prescribed medication (20), lifestyle factors (smoking, coffee, alcohol), DQG%0, QRUPDOZHLJKW%0, RYHUZHLJKWREHVH ,Q addition, urinary urgency (often or always, scale: never-rarely-oftenDOZD\V VWUHVVXULQDU\LQFRQWLQHQFH RIWHQRUDOZD\V DQGVQRULQJ nights/week) were considered as potential risk factors (using DAN-PSS and BNSQ). Age, socio-demographic and female reproductive factors (parity, menopause, hormone therapy, hysterectomy) were treated as potential confounders. All factors associated (p<0.10) with nocturia in the age-adjusted analyses were entered into the multivariate model. Backward elimination techniques were used to select variables for WKH¿QDOPRGHORIQRFWXULDZLWKOLNHOLKRRGUDWLRWHVWVXVHGWRGHWHUPLQH VLJQL¿FDQFH p<0.05). Then, elimination of confounders was performed FKDQJHLQWKHHVWLPDWHZDVGHHPHGFRQIRXQGLQJ 5(68/76 VXEMHFWV WRRN SDUW ZHUH excluded due to pregnancy, puerperium, or urinary tract infection. A number of conditions and medications were found as candidates for multivariate analysis. Several independent risk factors were found in the multivariate analyses (separately performed for men and women) (Table). Even though urgency was the strongest risk factor, majority of nocturia was not associated with urgency (Figure). Again, majority of urgency was associated with nocturia.